Adamantane carboxylic acid esters of chloramphenicol

ABSTRACT

ADAMANTANE CARBOXYLIC ACID ESTERS OF CHLORAMPHENICOL ARE PROVIDED WHICH ARE USEFUL AS ANTI-BACTERIAL AGENTS.

United States Patent 3,767,694 ADAMANTANE CARBOXYLIC ACID ESTERS 0FCHLORANEPHENICOL Venkatachala L. Narayanan, Hightstown, and Rudiger D.Haugwitz, Highland Park, N.J., assignors to E. R. Squibb & Sons, Inc.,New York, N.Y. No Drawing. Filed Jan. 6, 1971, Ser. No. 104,471

7 Int. Cl. C07c 69/74, 69/76 US. Cl. 260468 G 9 Claims ABSTRACT OF THEDISCLOSURE Adamantane carboxylic acid esters of chloramphenicol areprovided which are useful as anti-bacterlal agents.

The present invention relatesto adamantane carboxylic acid esters ofchloramphenicol having the structure wherein X is a single bond oralkylene or alkenylene, and can be attached at the 1 or 2 position ofthe adamantane ring, -R can be halogen, lower alkyl, lower alkoxy orphenyLandn is 0, 1 or 2.

X represents a straight or branched chain bivalent a11- phatichydrocarbon group, namely, an alkylene group or an alkenylene grouphaving from one to about six carbon atoms in the linking chain, such asmethylene, ethylene, propylene, butylene, dimethylethylene,l-propylbutylene, 1,2-diisopropylpentylene, 1 -ethyl2-buty1hexylene aswell as any of the above includinga double bond in the linking chainsuch as ethenylene, l-propenylene, and 2- butenylene and the like.

The term lower alkyl as employed herein includes both straight andbranched chain radicals of up to eight carbon atoms, 'for instance,methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl,hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, and the like.

The term halogen includes F, Br, C1 or I.

The term lower alkoxy includes straight and branched chain radicalswhich correspond to the above lower alkyl groups attached to an oxygenatom.

Preferred are those compounds wherein X is a single bond, R is H, andthe adamantyl ring is joined at the 1- position.

From the following description it will be apparent to those skilled inthe art that the l-p-nitrophenyl-2-dichloroacetamidopropane-1,3-diolused as a starting material and the ester products of the inventionexist in structural or diastereoisomeric as Well as optical isomericform. The present invention is concerned with compounds having the threodiastereoisomeric as distinguished from the erythro diastereoisomericform. The groups on the two asymmetric carbon atoms of such threodiastereoisomers have the same relative special configuration orarrangement as the groups on the two asymmetric carbon atoms of pseudoephedrine and threose.

Because of the difficulty in representing these structural-difierencesin graphic formulae, the customary structural formulae are used in boththe specification and claims. However, unless otherwise indicated theformulae are to be interpreted in their generic sense, that is, asrepresenting the D-threo and L-threo isomers in separated form as wellas the racemic mixture thereof.

Examples of compounds falling within the present invention include, butare not limited to, the following:

D-threo-2,2-dichloro-N- fi-hYdIOXY-u- (hydroxymethyl )-p-nitrophenethyl]acetamide, CL- (S-methyl- 1- adamantaneacrylate) ester;

L-threo-2,2-dichloro-N- fl-hydroxyoc- (hydroxymethyl) -p-nitrophenethyl]acetamide, a- S-fluorol-adamantanemethacrylate) ester;

D-threo-2,2-dichloro-N- [fi-hYClIOXY-a-(hydroxymethyl)-p-nitrophenethyl] acetamide, a-3-chlorol-adamantanecarboxylate) ester;

L-threo-2,2-dichloro-N- 3-hydroxy-a (hydroxymethyl) -p-nitrophenethyl]acetamide, oc- (3-iodo-1- adamantanecarboxylate) ester;

L-threo-2,2-dichloro-N- [B-hydroxy-a- (hydroxymethyl) -p-nitrophenethyl]acetamide, u- (3-bromol-adamantanebutylate) ester;

D,L-threo-Z,2-dichloro-N- [fl-hydroxy-a- (hydroxymethyl)-p-nitrophenethyl] acetamide, a- (3-methoxyl-adamantanecarboxylate)ester;

L-threo-2,2-dich1oro-N- fi-hydroxy-a- (hydroxymethyl -p-nitrophenethyl]acetamide, a- (3 -phenyl-1- adamantanecarboxylate) ester;

D-threo-2,2- dichloro-N- ,B-hydroxy-ahydroxymethyl-p-nitrophenethyl]acetamide, a- (3,5-dimethyll-adamantanecarb oxylate) ester;

D,L-threo-2, 2-dichloro-N- [B-hYClIOXY-ahydroxymethyl -p-nitrophenethyl]acetamide, a- (Z-adamantaneacetic acid) ester;

L-threo-2,2-dichloro-N- [p-hydroxy-a-hydroxy- (methyl)-p-nitrophenethyl] acetamide, (A ,a-2-adamantaneacetic acid) ester;

L-threo-2,2-dichloro-N- [B-hydroxy-a-h'ydroxy-(methyl)-p-nitrophenethyl] acetamide, u-(4-methyl- Z-adamantaneaceticacid) ester;

D,L-threo-2,2-dichloro-N- [B-hydroxya- (hydroxymethyl)-p-nitrophenethyl] acetamide, a- (Z-adamantanecarb oxylate) ester.

ll OH NHCCHC1 l 0 N CH-CH-CH 01-! (II) 2 2 with an acyl halide of thestructure III in a molar of IIzIII of within the range of from about1.811 to about 1:1.

The reaction is carried out under anhydrous conditions in the presenceof a basic catalyst such as pyridine, triethylamine, N,N-dimethylanilineor N-ethylpiperidine, at a temperature within the range of from about 20to about 35 Alternatively, a solution of II and III in a hydrocarbonsolvent like benzene is refluxed for 2-5 hr. without any basic catalyst.

Among the suitable acyl halide reactants may be mentioned thel-adamantane acid halides such as l-adamantanecarboxylic acid chloride,3 methyl 1 adamantanecarboxylic acid chloride, 3 fluoro 1adamantanecarboxylic acid chloride, 3 chloro 1 admantaneacrylic acidbromide, 3-bromo l adamantanecarboxylic acid chloride, 3 iodo 1adamantanecarboxylic acid iodide, 3 methoxy 1 adamantanepropionic acidchloride, 3-phenyl 1 adamantanecarboxylic acid chloride, 3,5 dimethyl 1adamantanebutyric acid chloride, 2-

adamantanecarboxylic acid chloride, l-adamantylacetyl chloride, 2 (ladamantyl)propionyl chloride, A ,ot- (adamantaneacetic acid chloride), 2adamantaneacetic acid chloride and 4 methyl 2 adamantaneacetic acidchloride.

All of the acyl halides described hereinbefore may be prepared byheating an acid of the formula m c-x wherein X and n are as hereinbeforedefined, with two parts by weight of a thiony-l halide, preferablythionyl chloride or thionyl bromide, alone, or in the presence of ananhydrous solvent, such as chloroform or benzene, under reflux for aperiod of up to three hours, concentrating to remove the excess thionylhalide (and any solvent present), and then distilling or recrystallizingto obtain the resultant acyl halide.

The above starting materials can be employed in the form of theircorresponding salts as will be apparent to one skilled in the art.

The new compounds of Formula I are useful as antimicrobial agents andmay be used to combat infections in animal species, such as mice, rats,dogs, pigs, guinea pigs, and the like, due to organisms such as Trichomonas vaginalis, T richomonas foetus, Staphylococcus aureus,Salmonella schottmuelleri, Salmonella choleraesius, Klebsiellapneumoniae, Proteus vulgaris, Escherichia coli, C. albz'cans, Trichophymn mentagrophytes or Pasteurella multocida. For example, acompound or mixture of compounds of Formula I may be administered orallyto an infected animal, e.g., to a mouse, in an amount of about 5 to 250mg. per kg. per day in 2 to 4 divided doses. These may be conventionallyformulated in a tablet, capsule or elixir containing about to 250 mg.per dosage unit, by compounding the active substance or substances withthe conventional excipient, vehicle, binder, preservative, flavor, etc.,as called for by accepted pharmaceutical practice. They may also beapplied topically, e.g., to dermatophytosis in a guinea pig, in alotion, salve or cream at a concentration of about 0.01 to 3 percent byweight. They may also be used in the prophylactic treatment of scours insmall pigs.

They may also be used as surface disinfectants. About 0.01 to 1 percentby weight of any of these substances may be dispersed on an inert solidor in a liquid such as water and applied as a dust or spray. They may beincorporated also, for example, in a soap or other cleansing agent,e.g., a solid or liquid detergent, detergent composition, for example,in general cleaning, in cleaning dairy barns or equipment or cleaningfood handling or processing equipment.

The following examples further illustrate the invention.

EXAMPLE 1 D-threo 2,2 dichloro-N-[fi-hydroxy or. (hydroxymethyl) pnitrophenethyflacetamide, a (l-admantanecarboxylate)ester To a solutionof 4.0 g. of D-threo 2,2 dichloro-N- [fl-hydroxy a (hydroxymethyl) pnitrophenethyl] acetamide in 50 ml. of pyridine, 2.5 g. ofl-adamantanecarboxylic acid chloride is added and the solution stirredfor 72 hrs. The reaction mixture is poured onto ice Water. The thick oilis separated and dissolved in 200 ml. of ether. The ethereal solution iswashed successively with water, dilute Na CO solution, water, dilute HCland water. Evaporation of the dried ethereal solution gives a thick oil,which crystallizes on layering with pentane and scratching (4.2 g.).Recrystallization from etherpentane gives an analytical sample, M.P.76-79", shrinks at 73.

4 Analysis.-Calcd. for c H N O Cl (percent): C, 54.48; H, 5.40; N, 5.78.Found (percent): C, 54.24; H, 5.50; N, 5.62.

EXAMPLE 2 L-threo 2,2 dichloro N [fi-hydroxy u (hydroxymethyl) pnitrophenethyl] acetamide, ct (l-admantanecarboxylate) ester Followingthe procedure of Example 1, but substituting L-threo 2,2dichloro-N-[fl-hydroxy a (hydroxymethyl) p nitrophenethyllacetamide forD-threo-2,2- dichloro N 3 hydroxy a(hydroxymethyl)-pnitrophenethyl1acetamide, the title compound isobtained.

EXAMPLE 3 D.L-threo 2,2 dichloro N {fi-hydroxy a (hydroxymethyl) pnitrophenethyHa-cetamide, a (l-admantanecarboxylate)ester Following theprocedure of Example 1, but substituting D,L-threo 2,2 dichloro N[fi-hydroxy or (hydroxymethyl) p nitrophenethylJacetamide forD-threo-2,2- dichloro N {B hydroxy a (hydroxymethyl)pnitrophenethyllacetamide, the title compound is obtained.

EXAMPLE 4 D-threo 2,2 dichloro N [fl-hydroxy a (hydroxymethyl) pnitrophenethyl]acetamide,ot-(2-adamantanecarboxylate)ester Following theprocedure of Example 1, but substituting Z-adamantanecarboxylic acidchloride for l-adamantanecar'boxylic acid chloride, the title compoundis obtained.

EXAMPLE 5 D-threo 2,2 dichloro N s-hydroxy a. hydroxymethyl) pnitrophenethynacetamide, a (l-admantaneacrylate)ester (A)l-adamantanemethanol: To a well-stirred suspension of 15 g. of lithiumaluminum hydride in 500 ml. of dry ether, a solution of 54.0 g. (0.3mole) of l-adamantanecarooxylic acid in 500 ml. of dry ether is added atsuch a rate as to maintain gentle reflux (addition time 2.5 hrs.). Themixture is stirred overnight at room tem perature. After cooling, 75 ml.of distilled water is added cautiously followed by 300 ml. of 5 N H and500 ml. of ether. The ethereal layer is separated, and the aqueous layeris extracted once with 300 ml. of ether. The ether layers are combined,washed with water, saturated sodium bicarbonate solution, and again withwater and dried over anhydrous MgS-O Evaporation of ether gives 46.9 g.of l-adamantanemethanol as white crystals, M.P. 114-115";

ml? 3.05,. on 9.5,. (0-0) (B) l-adamantaldehyde: l-adamantanemethanol33.2 g. (0.2 mole), is dissolved in 700 m1. of reagent grade acetone andcooled to 0 (-5). Freshly made 8 N Jones Reagent (60 ml.) is addeddropwise with stirring at such a rate as to maintain the temperature ofmixture at 810 (addition time 40 min). After the addition, the coolingbath is removed and the mixture stirred for 10 min. Methanol (50 ml.) isadded to the bluish green solution. The separated solids are dissolvedby the addition of 700 ml. of Water and stirring. The solvent is removedin vacuo, and the aqueous layer is extracted with 3x 50 m1. of ether.The combined ethereal extract is washed once with water, twice with sat.solution of NaHCO, ml.), once again with water. After drying thesolution is concd. in vacuo to give 24.8 g. (76%) of crude1-adamantaldehyde as a thick oil.

(0. I-adamantaneacrylic acid ethyl ester: Triethylphosphonoacetate (44.8g., 0.2 mole) is added dropwise at 20 to a slurry of sodium hydride (9.6g.) in 500 ml. of dry dimethoxyethane (addition time 1.5 hrs.). Themixture is stirred for 2 hr. at room temperature. l-adamantaldehyde(24.6 g., 0.15 mole) dissolved in 200 ml. of dry dimethoxyethane, isadded dropwise at room temperature to the above reaction mixture, andstirred overnight. The mixture is then refluxed for an hour. Afterremoving the solvent in vacuo, the mixture is diluted with 1000 ml. ofwater and'eXtracted-With-S x 300 ml. of ether. The ethereal layers arecombined, dried (MgSO and concd. to give 28.4 g. (81%) of the titlecompound as a clear yellow liquid, A 5.8 2 (ester 0:0), 6.08 (conj.alkene).

(D) l-adamantaneacrylic acid: A stirred mixture of 23.4 g. (0.1 mole) ofthe product from step (C), 250 ml. of 25% KOH solution, and 100 ml. ofethyl alcohol is refluxed for 3 hrs The reaction mixture is cooled,concd. in vacuo, and diluted with 250-ml. of water. The postassium saltof the acid that precipitates is collected (16.4 g.), dissolved in 100ml. of alcohol, cooled, and acidified with dil. HCl. The crude solidobtained after removal of the solvent is crystallized frommethanol-water to give 8.3 g. (40%) of the title compound as pale yellowcrystals, M.P. 170-172", shrinkingseveral degrees before meltmg.

Analysis.-Calcd. for C H O (percent): C, 75.69; H, 8.80. Found(percent): C, 75.85; H, 8.50. Neutralization equivalent: Calcd., 206.27.Found, 207.8.

(E) l-adamantaneacr'ylic acid chloride: A mixture of g. ofl-adamantaneacrylic acid and 20 ml. of thionyl chloride is heated underreflux-for.30 min. The excess thionyl chloride is removed in vacuo. Tenml. of anhydrous benzene is added to the residue and the solvent isremoved by distillation in vacuo. The residue crystallizes to a solidmass and is used without further purification.

(F) D threo-2,2-dichloro-N-[fi-hydroxy-a-(hydroxya-(hydroxymethyl) pnitrophenethyl]acetarnide,a-(1- adamantaneacrylat) ester: Following theprocedure of Example 1, but substituting l-adamantaneacrylic acidchloride for l-adamantanecarboxylic acid chloride the title compound isobtained.

EXAMPLE '6 D threo 2,2 dichloro N [,8 hydroxy a (hydroxymethyl) pnitrophenethyl]acetamide t (A ,aadamantane-acetic acid)ester (A)Z-adamantanone: A mixture of 100 ml. of cone. H SO and 24.6 g. (0.16mole) of l-hydroxyadamantane is heated with stirring on the steam bathfor 4.5 hrs. At the end of the period, the dark red solution is pouredonto crushed ice, and the mixture is extracted with 300 ml. of ether.After was'hing'the ether layer to neutrality, it is dried (MgSOEvaporation ofi'the ether gives 15.0 g. (62%) of Z-adamantanone as awhite solid which is further purified by steam distillation followed bycrystallizationfrom cyclohexane;M.P. 260-265.

(B) A ,a-adamantaneacetic acid, ethyl ester: To a wellstirred suspensionof 2.8 g. of sodium hydride dispersed in 75 ml. of dryl,2-.dimethoxyethane, 13.45 g. (0.06

mole) of triethylphosphonoacetate are added dropwise at 20 (additiontimel hr.). After the addition, the mixture is stirred for an hour atroom temperature. To the resulting yellow solution, a solution of 9.0 g.(0.06 mole) of Z-adamantanone in 75 ml. of dry 1,2-dimethoxyethane isadded at such a rate as to maintain the temperature between 28-30. Themixture is then stirred overnight at room temperature. The mixture isconcentrated, diluted with 100 ml. of water, and extracted with 3X 300ml. of ether. After drying (MgSO the ether is removed in vacuo to give10.3 g. (77%) of A ,a-adamantaneacetic acid, ethyl ester, as a thick oilwhich is used as such for the next step.

(C) A ,o=-adamantaneacetic acid: To a solution of 10.3 g. of the productof part (B) in 250 m1. of ethyl alcohol, 150 ml. of an aqueous KOHsolution (25 is added and the mixture heated under reflux for 4 hrs. Themixture is concentrated in vacuo, diluted with water and extracted withwater and extracted with chloroform (200 ml.) to remove the insolubleimpurities. The basic solution is cooled, acidified with 5 N HCl, andthe solid which separates is extracted with chloroform (3x 250 ml.). Thechloroform solution is washed with Water, dried (MgSO and evaporated invacuo to give 6.8 g. (79%) of A ,a-adamantaneacetic acid (yellowishneedles); M.P. 136-138.

(D) A ,u-adamantaneacetic acid chloride: To a solution of 3 ml. ofoxalyl chloride in 25 ml. of dry benzene, a solution of 0.06 g. (0.005mole) of the product of part (C), in 25 ml. of dry benzene is added.After the initial evolution of gas has subsided, the reaction mixture isstirred and heated to reflux for an hour. The solvent is removed invacuo, 25 ml. of dry ether is added to the residue, and the solvent isevaporated to give a thick oil which solidifies to a semi-solid.

(E) D threo 2,2 dichloro N [B hydroxy u- (hydroxymethyl) pnitrophenethyl]acetamide,a-(A ,aadamantaneacetic acid)ester: Followingthe procedure of Example 1, but substituting A ,u-adamantaneacetic acidchloride for l-adamantanecarboxylic acid chloride the title compound isobtained.

EXAMPLE 7 D-threo-2,2-dichloro-N- [B hydroxy-a-(hydroxymethyl)- pnitrophenethyl]acetamide,oc-(2 adamantaneacetic acid)ester (A) A,ot-adamantaneacetonitrile: To a well-stirred suspension of 14.5 g. (0.6mole) of 50% sodium hydride in 300 ml. of dry 1,2-dimethoxyethane, 53 g.(0.3 mole) of diethylcyanomethylphosphonate is added dropwise at 20.After the addition, the mixture is stirred at room temperature for 2hrs. To the resulting yellow solution, a solution of 30 g. (0.2 mole) ofadamantanone in 300 ml. of dry 1,2-dimethoxyethane is added during 0.25hr. The temperature of the reaction mixture rises to 45. The reactionmixture is refluxed with stirring for 1.5 hrs. The mixture is cooled,concentrated, diluted with water and extracted with ether. After drying(MgSO the ether is removed in vacuo to give 39.6 g. of A,a-adamantaneacetonitrile; M.P. 64.69;

trile, M.P. 3739. An analytical sample crystallized from pentane meltsat 42-43";

X23 45, (C=N), no conjugated C=C at 6.15; '1' CDCI none at 5.0 (absenceof vinyl protons).

Analysis.-Calcd. for C12H17N (percent): C, 82.22; H, 9.78; N, 7.99.Found (percent): C, 81.97; H, 9.64; N, 7.71.

(C) Z-adamantaneacetic acid: A solution of 6.5 g. ofZ-adamantaneacetonitrile and 9 g. of sodium hydroxide in 50 ml. ofalcohol is refluxed overnight. The solution is concentrated in vacuo,diluted with water and extracted with CHCl The aqueous layer is cooled,acidified, and extracted with chloroform. Evaporation of chloroformgives 5.19 g. of Z-adamantaneacetic acid, M.P. 118-120".

(D) Z-adamantaneacetic acid chloride: A mixture of 10 g. ofZ-adamantaneacetic acid and 20 ml. of thionyl chloride is heated underreflux for 30 min. The excess of thionyl chloride is removed in vacuo,10 ml. of dry benzene is added to the residue and solvent removed invacuo. The residue crystallizes and is used without furtherpurification.

(E) D-threo 2,2dichloro-N-[fi-hydroxy-u-(hydroxymethyl)-p-nitrophenethyl]acetamide z (2adamantaneacetic acid)ester: Following the procedure of Example 1, butsubstituting 2-adamantaneacetic acid chloride for 1-adamantanecarboxylic acid chloride the title compound is obtained.

EXAMPLES 8 TO 12 Similarly employing the procedure of Example 1, butsubstituting the following R-substituted-adamantanecarboxylic acidhalide for l-adamantanecarboxylic acid chloride the corresponding estersare obtained.

133 NH?! CHCl' 2 cancra ox-@ -tal wherein X is a single bond or alkyleneor alkenylene, containing 1 to 6 carbons, and is attached at the lor 2-position of the a-damantane ring, R is selected from the groupconsisting of halogen, lower alkyl, lower alkoxy or phenyl, n is 0, l or2, where X is attached at the lposition of the adamantane, R can beattached at the 3- and/or 5-positi0n thereof, Where X is attached at the2- position of the adamantane ring, 11 is 0 or 1 and R is attached atthe 4- or -position thereof.

2. A compound in accordance with claim 1 having the structure I. OHNHLICHCl including D-threo, L-threo and DL threo isomers.

3. A compound in accordance with claim 1 having the structure n H.NHccI-Icl o including all threo isomers thereof.

4. A compound in accordance with claim 1 having the structure 0 OHNHccHc L 0 including all threo isomers thereof.

5. A compound in accordance with claim 1 having the structure ll palilHccHcl g o n -cacaca o c ca including all threo isomers thereof.

6. A compound in accordance with claim I, having the structure 0 u onTHCCHCIZ o l n O2N-@ cacae3 -,-o c

and its threo isomers.

7. A compound in accordance with claim 1, having the structure OC H andits threo isomers.

8. A compound in accordance with claim 1, having the structure 9. Acompound in accordance with claim 1, having the structure 5 0Huncoc'ac].

l l R O2N-- CH- CH- CH2 '5 0-- C-- and its threo isomers.

References Cited UNITED STATES PATENTS 2,662,906 3/ 1951 Edgerton260-404 FOREIGN PATENTS 672,672 3/1966 Belgium 260-477 OTHER REFERENCESFort, In, et al., Chem. Rev., 64, pp. 297-8 (1964).

LORRAINE A. WEINBERGER, Primary Examiner R. GERSTL, Assistant ExaminerUS. Cl. X.R.

260469, 514G, 515R, 562C; 424-299

